Figure 1. Model of glucocorticoid-induced hepatic insulin resistance.

In Angptl4 expressing mice (Angptl4+/+), dexamethasone (a synthetic glucocorticoid) induces the expression of genes encoding enzymes in ceramide synthesis, such as Spt1/2 and Cers3-6, to increase hepatic ceramide production, which activates PP2A and PKCζ to inhibit Akt to cause hepatic insulin resistance. In Angptl4 null mice (Angptl4-/-), the ability of dexamethasone to augment Cers3-6 expression is impaired, which results in reduced ceramide levels and lower PP2A and PKCζ activity. As a result, hepatic insulin sensitivity is improved. Angptl4 stimulates lipolysis in white adipose tissue and also inhibits lipoprotein lipase (LPL) activity in circulation. It is unclear which of these functions is responsible for its action in glucocorticoid-induction hepatic ceramide production.